Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease

Abstract

Objectives: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI).Methods: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n ϭ 566). Regression analysis showed CSF A␤42 levels and t-tau/A␤42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. Conclusion:Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study. Neurology The clinical diagnosis of mild cognitive impairment (MCI) and probable Alzheimer disease (AD) is increasingly aided by biomarkers predictive of underlying pathology.1,2 These include CSF biomarkers reflecting the plaque and tangle pathology underlying AD such as ␤-amyloid 1-42 (A␤42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau 181 ) 3 ; substratespecific brain imaging such as 11 C and 18 F PET imaging 4,5 ; and structural MRI findings such as hippocampal volume.6 Each modality has a different sensitivity-specificity profile, and additional technical barriers and patient preferences may dictate the successful implementation of any biomarker into clinical practice, including aversion to having a lumbar puncture for CSF biomarkers and cost for advanced imaging. Thus, a blood-based test is an appealing alternative because of its simplicity and cost-effectiveness for widespread clinical use as well as in specialty centers.7,8 A multi-analyte profiling approach to plasma proteins and peptides can also yield †Deceased.